A CPIC dosing guideline, not a research finding still waiting for use: TPMT and NUDT15 genotype already guide starting doses of azathioprine, mercaptopurine and thioguanine in hospitals that test for it, through two separate genetic pathways to the same risk.
Thiopurines -- azathioprine, mercaptopurine and thioguanine -- are immunosuppressant drugs used to treat leukemia, inflammatory bowel disease, and to prevent organ transplant rejection. Their dose window is narrow: too little under-treats the disease, too much causes severe, sometimes life-threatening myelosuppression (bone marrow suppression, leaving someone dangerously short on white blood cells, red blood cells or platelets). Two separate genes, acting through two separate mechanisms, are established enough that a professional guideline body now recommends adjusting the starting dose based on genotype.
rs1142345 is the TPMT*3C allele, catalogued here. TPMT (thiopurine methyltransferase) is the enzyme that metabolizes thiopurines; a reduced-function variant means less breakdown, more active drug staying in the body longer, and a real, well-established increase in toxicity risk at a standard dose.
rs116855232 is the NUDT15*3 allele, catalogued here. NUDT15 works differently from TPMT -- it degrades the drug's own active metabolites once they are already inside the cell, so a loss-of-function variant leaves more active drug in circulation through a mechanism entirely separate from TPMT's. NUDT15 loss-of-function alleles are common specifically in people of Asian and Hispanic ancestry, populations in whom TPMT variants alone were historically found to under-explain thiopurine toxicity -- discovering NUDT15 filled a real gap the TPMT-only picture left.
The guideline behind this page, from the Clinical Pharmacogenetics Implementation Consortium (CPIC), gives specific starting-dose adjustment recommendations by combined TPMT/NUDT15 genotype -- the kind of guidance clinical laboratories and hospital pharmacogenomics programs already use when a patient's genotype is known before a thiopurine prescription is written.
TPMT and NUDT15 genotyping, where available, informs a starting dose before a thiopurine is first prescribed -- it does not replace the routine blood-count monitoring every patient on these drugs already gets, which remains the direct way toxicity is caught regardless of genotype. The specific dose adjustments are a clinical decision made by the prescribing physician, guided by the CPIC recommendations and the patient's full clinical picture, not something to self-interpret from a genotype alone.
This is guideline information, not a personal dosing instruction. The CPIC guideline gives dose-adjustment ranges by genotype for a prescriber to apply; it does not set an individual's dose by itself, and thiopurine dosing decisions should always be made with the treating physician.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Thiopurine Dosing (TPMT and NUDT15) comes down to these specific, well-studied positions — not a diagnosis.
Databases, guidelines and references
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Thiopurine Dosing (TPMT and NUDT15). MyGeneLog™. https://www.mygenelog.com/conditions/thiopurine-dosing
No. It describes what CPIC's published guideline recommends based on genotype, for a prescribing physician to apply -- an individual's actual dose is a clinical decision made with the treating physician, not something to determine from this page.
Thiopurines: azathioprine, mercaptopurine and thioguanine -- used for leukemia, inflammatory bowel disease, and after organ transplant.
No. They are two separate genes acting through two separate mechanisms that both affect thiopurine toxicity risk -- TPMT breaks the drug down, NUDT15 degrades its active metabolites once inside the cell. A genotype at one does not predict the other.
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